Defining the role of glucocorticoid-related dendritic spine plasticity in cocaine-induced habits

项目摘要 目标导向行动指的是根据期望的结果选择行动的能力。与目标形成对比的是- 定向的行动，习惯是由刺激引起的，对目标不敏感。目标导向的行动和习惯都是 对生存很重要，但习惯可能是不适应的，是许多神经精神疾病的特征 包括可卡因使用障碍(CUD)。首份报告称可卡因导致人们以牺牲为代价养成习惯 关于啮齿动物目标导向作用的研究在大约15年前发表，但其潜在的机制仍不清楚。 可卡因会导致应激激素的释放，而可卡因和应激激素的暴露都会导致 眼眶额叶皮质(OFC)树突棘的不稳定。对啮齿动物的研究也表明，当地 药物的注入破坏了OFC中树突棘的稳定，扰乱了目标导向的行动，导致了对 习惯性行为。研究人员将检验长期接触可卡因会导致习惯的假设 通过增加循环应激激素水平，激活糖皮质激素受体(GR)， 导致OFC中的树突棘突丢失。因此，调查员将确定可卡因 导致习惯偏见。 在目标1中，研究人员将使用体内病毒介导的基因沉默和一项被称为“工具性”的任务 “偶然性退化”，测试小鼠将训练的反应与其可能的结果联系起来的能力。 调查者将由此确定可卡因是否会降低目标导向的行为(导致习惯偏差)。 通过长时间刺激OFC中的GRs。调查人员假设，长期接触可卡因 通过触发皮质醇释放来诱导习惯，导致OFC中GRs的慢性激活。因此，减少GR OFC中的水平将防止可卡因诱导的习惯性行为。 在目标2中，研究人员将使用药理学技术直接操纵肌动蛋白细胞骨架。 在OFC内选择性地确定细胞骨架稳定性在OFC依赖的目标导向行动中的作用。 研究人员假设，刺激树突状棘突的发生将促进目标导向的行动 暴露于可卡因的小鼠，虽然破坏树突棘的稳定，但将阻断这一效应。 人们普遍认为，精神刺激剂和压力改变了树突和树突棘的密度，并 形态，然而与滥用药物或应激源的行为影响的因果关系在很大程度上不是 已验证。因此，通过执行这项拟议的工作，调查员将解决基本的未回答问题 关于应激激素和树突棘可塑性如何影响可卡因方式的问题 改变复杂的决策。这项研究具有很高的翻译性，可能会揭示治疗的新方法 CUD，目前还没有针对这种疾病的药物疗法，同时也为调查人员配备了技能 对于一个成功的科学事业来说是必要的。

Project Summary Goal-directed action refers to the ability to select an action based on a desired outcome. In contrast to goal- directed actions, habits are stimulus-elicited and insensitive to goals. Both goal-directed action and habits are important for survival, but habits can be maladaptive and are characteristic of many neuropsychiatric diseases including cocaine use disorder (CUD). The first report that cocaine causes a bias towards habits at the expense of goal-directed action in rodents was published ~15 years ago, but the underlying mechanisms remain unclear. Cocaine causes the release of stress hormones, and both cocaine and stress hormone exposure cause the destabilization of dendritic spines in the orbitofrontal cortex (OFC). Research in rodents also indicates that local infusion of drugs that destabilize dendritic spines in the OFC disrupts goal-directed action, causing a bias towards habitual behavior. The investigator will test the hypothesis that chronic cocaine exposure causes habit biases by increasing levels of circulating stress hormones, activating glucocorticoid receptors (GR), leading to dendritic spine loss in the OFC. The investigator will thus identify mechanisms by which cocaine induces habit biases. In Aim 1, the investigator will use in vivo viral-mediated gene silencing and a task termed “instrumental contingency degradation”, which tests the ability of mice to associate a trained response with its likely outcome. The investigator will thereby determine whether cocaine degrades goal-directed action (causing habit biases) via prolonged stimulation of GRs in the OFC. The investigator hypothesizes that prolonged cocaine exposure induces habits by triggering CORT release, causing chronic activation of GRs in the OFC. Thus, reducing GR levels in the OFC will protect against cocaine-induced habitual behavior. In Aim 2, the investigator will use pharmacological techniques to directly manipulate the actin cytoskeleton selectively within the OFC to determine the role of cytoskeletal stability in OFC-dependent goal-directed action. The investigator hypothesizes that stimulating dendritic spinogenesis will promote goal-directed action in cocaine-exposed mice, while destabilizing dendritic spines will block this effect. It is widely accepted that psychostimulants and stress modify dendrite and dendritic spine densities and morphologies, yet causal relationships with the behavioral effects of drugs of abuse or stressors are largely not verified. Thus, by carrying out this proposed work, the investigator will address fundamental unanswered questions regarding how stress hormones and dendritic spine plasticity influence the manner in which cocaine alters complex decision making. This research is highly translational and could reveal new approaches to treating CUD, for which no pharmacotherapies currently exist, while also equipping the investigator with the skills necessary for a successful scientific career.